Protein tyrosine kinases (PTK) are critical enzymes for receptor-mediated signal transduction in lymphocytes. Indeed, protein tyrosine phosphorylation is an early and requisite event in signaling for both multichain immune recognition receptors such as the T-cell antigen receptor (TCR) and cytokine receptors. Unlike growth factor receptors, neither the TCR nor the cytokine receptors have intrinsic PTK activity. Rather, they are coupled to nonreceptor tyrosine kinases. For example, the src family PTK, Lck and Fyn have been implicated in TCR-mediated signaling. The non-src family PTK Zap-70 has been shown to associate with the TCR upon activation. The src family PTK, Lck, Fyn and Lyn have also been implicated in Interleukin-2 (IL-2) receptor mediated signaling.
The Janus family kinases (JAKs) represent a recently described family of PTK. These kinases, called JAK-1, JAK-2 and Tyk-2, are structurally quite distinct in that they possess tandem nonidentical catalytic domains. These PTK are ubiquitously expressed and have been shown to participate in signaling by a number of cytokine and hormone receptors. These PTK are believed to exert their effects through tyrosyl phosphorylated transcription factors.
IL-2 is a T-cell lymphokine that both functions as a potent autocrine growth factor and activates other cells, including B-cells and natural killer (NK) cells. In addition, the interaction of IL-2 with high affinity IL-2 receptors regulates the magnitude and duration of the normal T-cell immune response.
High affinity IL-2 receptors comprise three receptor components, denoted the IL-2 receptor α, β and the common γ (γc) chain. Interestingly, the γc chain is a receptor component that is shared by the receptors for several of the interleukins. In the mechanism of IL-2 signal transduction, IL-2 binding induces heterodimerization of the cytoplasmic domains of β and γc. This heterodimerization is required for IL-2 signaling.
While the IL-2 receptor is a multi-subunit complex that lacks intrinsic enzymatic activity, it is clear that protein tyrosine phosphorylation is an early biochemical step that follows ligand binding. Occupancy of the IL-2 receptor additionally stimulates alkalinization of T-cells via Na+/H+ exchange, activation of Ras, Raf and ERK1, induction of the fos, jun and myc proto-oncogenes, as well as induction of effector functions such as cytotoxicity and cellular proliferation.